Submassive PE: Are we treating it backwards?

Introduction

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Submassive PE can be challenging. Most patients do fine with heparin, but occasional patients suddenly arrest and others are left with longstanding pulmonary hypertension.1 Thrombolytics generally cause dramatic improvement, but may cause hemorrhage as well. Recent studies may seem to point in opposite directions.

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Background: Heparin vs. Alteplase

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Treatment centers around two drugs: heparin and alteplase. Heparin is not actually supported by high-quality evidence, having been introduced in the era before evidence-based medicine.2Heparin prevents formation of additional clot, but doesn’t lyse existing clot. Heparin has been enthusiastically embraced by the medical establishment and is perceived to be safe, although it is quite capable of causing intracranial hemorrhage (ICH).

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Unlike heparin, alteplase has been proven to cause acute improvement in PE with reduction in pulmonary pressure and decreased risk of cardiovascular collapse. However, the use of alteplase has been limited by the perception that it is a dangerous drug with a high risk of hemorrhage. This isn’t supported by the evidence. Combining RCTs of heparin +/- alteplase, there is no significant difference in ICH rate or major hemorrhage rate among the alteplase group:3,4

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Why do we think alteplase is so dangerous in PE? Well, alteplase does cause ICH in patients with ischemic stroke and myocardial infarction, but these are different patients with additional risk factors for ICH. Stroke patients have acutely injured brains which may hemorrhage spontaneously. Myocardial infarction patients are typically on a potpourri of anticoagulants. In contrast, PE patients have an underlying tendency to form clots. It’s not valid to extrapolate experience with thrombolysis in cardiac and neurologic patients to PE patients.

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The primary reason that we think alteplase is dangerous in PE may be confirmation bias. Conventional wisdom is that heparin infusions are safe, whereas alteplase is dangerous. Therefore, when a patient with PE receives heparin and alteplase, any bleeding is generally blamed on the alteplase (rather than the heparin, or the synergy of these two medications). This circular logic perpetuates the misconception that heparin is safe whereas alteplase is dangerous.

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Half-dose alteplase & MOPETT

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PE may be respond to lower doses of thrombolytics than MI for a variety of reasons, and studies have shown that lower doses of alteplase may be very effective in PE. “Half-dose” thrombolysis (50mg alteplase) has been investigated in three studies recently:

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Wang et al. 2010 performed a multi-center study of submassive or massive PE randomized to either 50mg or 100mg of alteplase infused over two hours. The improvements in pulmonary pressures, right ventricular dilation, and perfusion defects were nearly identical with either dose of alteplase. However, patients receiving 50mg alteplase experienced less bleeding. Of note, these authors first administered only alteplase, and initiated subcutaneous low-molecular weight heparin only after completion of thrombolysis when the aPTT value fell below 80 seconds.

Sharifi et al. 2014 reported a series of 98 patients with submassive PE treated with 50mg alteplase and heparin followed by oral riveroxiban. Patients did extremely well without any major or minor bleeding during hospitalization and with sustained improvement in pulmonary pressures. Although this is not a controlled trial, it supports the safety and efficacy of 50mg alteplase. This study avoided supratheraputic heparin infusions by reducing the rate of heparin infusion while administering alteplase and three hours thereafter and by omitting heparin boluses for PTT adjustment.

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Reduced-dose alteplase appears to have a good track record for safety:

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There is some debate regarding whether we should start using 50mg alteplase or await additional studies. My opinion is that considering the entire body of evidence supporting alteplase in PE there is sufficient justification for using 50mg alteplase in submassive PE on a case-by-case basis with shared decision making. It should be noted that the studies of half-dose thrombolytics described above used various measures to avoid combining thrombolysis with supratheraputic heparin infusions. Similar measures probably need to be implemented in general clinical practice to achieve the level of safety which these authors reported. A reasonable approach may be to reduce or hold the heparin infusion during thrombolysis and three hours thereafter, avoid heparin boluses following administration of thrombolytic, and target on aPTT of 1.5-2x upper limit normal for 24 hours following thrombolysis.

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TOPCOAT: Evaluating long-term patient-centered outcomes

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The MOPETT trial proves that 50mg alteplase causes a rapid and sustained reduction in pulmonary pressures compared to heparin alone. Critics have questioned whether this decrease was of any clinical significance. Patients with PE die due to acute dilation and failure of the right ventricle, so it stands to reason that reducing pulmonary pressures will reduce the likelihood of cardiovascular collapse. However, it has been unclear what symptomatic benefit patients would obtain from a reduction in pulmonary pressures months later.

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The TOPCOAT study randomized 83 patients with submassive PE to low molecular-weight heparin plus placebo or full-dose tenecteplase. The primary outcome was a composite including death, shock, intubation, major bleeding, recurrent PE, or poor functional capacity at 90 days. Patients in the placebo group met one of the composite endpoints more than twice as often as patients in the tenecteplase group (37% vs. 15%, p = 0.017). Patients treated with tenecteplase were discharged from the ICU and the hospital earlier with better long-term functional outcomes. Unfortunately the study was terminated early leaving it underpowered. Overall TOPCOAT supports the concept that thrombolytics improve both short-term and long-term outcomes.

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PEITHO: Full-dose tenecteplase for submassive PE?

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PEITHO, the largest study on submassive PE released in the New England Journal this month, randomized patients with submassive PE to heparin vs. heparin plus full-dose tenecteplase.6 These authors found a 2% rate of intracranial hemorrhage, which is higher than rates reported with alteplase:

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The rate of ICH with full-dose tenecteplase (12/574) is significantly higher than the combined rate observed in studies of reduced-dose alteplase (0/293; fisher exact score: p = 0.01).7 Additionally, rates of major bleeding were much higher in the tenecteplase group compared to the control group (11.5% vs. 2.4%, p < 0.001), in contrast to studies utilizing alteplase which have not demonstrated significant differences in major hemorrhage rate:4

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Why was there so much bleeding? The PEITHO study generally administered a tenecteplase bolus shortly following a heparin loading bolus, which may lead to transiently excessive levels of anticoagulation. Among patients receiving unfractionated heparin infusions, 36% had an initial aPTT value above 2.5x upper limit normal (Supplemental data, table S2). Additionally these authors titrated heparin infusions to target an aPTT of 2-2.5x upper limit normal, which is on the higher end compared to most heparin protocols and above the 1.5-2x upper limit normal aPTT target recommended by the MOPETT investigators to avoid hemorrhage.

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PEITHO does confirm that thrombolysis reduces the risk of cardiovascular collapse, a result previously obtained with alteplase. The real question is whether it is possible to achieve this benefit without a high risk of ICH. There is no evidence that heparin is acutely beneficial in PE, although heparin can certainly cause hemorrhage. In contrast, there is substantial evidence that thrombolytics cause immediate benefit. Therefore, it may make sense that heparin should be avoided in the peri-thrombolysis period to allow for administration of thrombolytic with reduced risk of hemorrhage. It’s also probable that lower doses of thrombolytic agent (i.e. 50mg alteplase) may achieve a similar benefit with less risk.

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The NEJM editorial accompanying PEITHO concluded that one way to approach patients with submassive PE would be close observation followed by rescue fibrinolysis if they deteriorate. Although this may work for some patients, it's not uncommon for patients with known PE to arrest and die while in the ICU, proving that close observation is not perfect. In PEITHO, increased death due to cardiopulmonary failure occured in the control arm despite rescue fibrinolysis being used for 23 patients in this group. The author of this editorial was unaware of recent research with half-dose thrombolytics, so perhaps he would have recommended this approach if he was better informed.9

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ULTIMA: Resurrection of catheter-directed thrombolysis?

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The ULTIMA study and additional studies in progress compare heparin to catheter-directed thrombolysis using a specially designed catheter which also emits ultrasound waves to disrupt the clot. 87% of patients in this study had bilateral pulmonary emboli, and therefore had bilateral catheters placed (!) with delivery of a total of 20 mg alteplase as a slow infusion over 15 hours. Patients who received alteplase had a reduction in right ventricular dilation.

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These industry-funded studies are difficult to interpret because it is impossible to sort out the effect of the thrombolytic vs. the effect of catheter delivery. The ideal dose of thrombolytic is unclear, and it is probable that small doses may be more effective than previously thought. To truly evaluate the efficacy of catheter-directed thrombolysis, a RCT is needed comparing catheter-directed thrombolysis to systemic administration of the same amount of thrombolytic or perhaps a higher amount (to account for dilution of peripheral thrombolytic en route to the lungs).

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Widespread use of an interventional approach to submassive PE would be problematic. Interventions are operator-dependent, and real-world results would probably be inferior to results obtained within a clinical study performed at large academic centers. Interventional therapy would be available at a limited number of hospitals. It may make more sense to focus on understanding medical treatments before abandoning medical therapy in favor of an invasive approach.

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Conclusions

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Our approach to treatment of submassive PE may be flawed based on a series of historical events. Heparin was introduced prior to the era of evidence-based medicine and universally adopted as first-line therapy despite no evidence of efficacy.2 Thrombolytics were introduced some decades later, by which time the use of heparin was so entrenched that it was inconceivable not to use heparin. Therefore, thrombolytics were tested in combination with heparin (heparin +/- thrombolytic) instead of being compared to heparin (heparin vs. thrombolytic). The combination of heparin and thrombolytics has at times led to hemorrhage which is invariably blamed on the thrombolytic (rather than the synergistic combination of thrombolytic plus heparin), causing clinicians to retreat back to the use of heparin monotherapy.

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This explains the paradoxes in our current treatment scheme. Although there is evidence supporting thrombolytics for the acute management of submassive PE compared with a lack of evidence supporting heparin, treatment typically consists of heparin. Although RCTs of pulmonary embolism patients do not show a substantial increase in ICH or major hemorrhage when alteplase is added to heparin, alteplase is nonetheless widely avoided due to concerns of causing hemorrhage. For patients without contraindication to thrombolytics, it may be more logical to use alteplase alone for initial therapy to lyse the clot followed later by anticoagulation to prevent recurrence. The safety of this approach may be further enhanced by using lower doses of alteplase and avoiding thrombolysis in patients at higher risk for ICH (i.e. >70-75 years old). Although this strategy of thrombolysis followed by heparin has been described in China, it is not the usual practice pattern in the US.7

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The PEITHO trial shows unusually high rates of ICH and major bleeding when patients were given consecutive boluses of full-dose tenecteplase and heparin, followed by a heparin drip targeting aPTT values 2-2.5x upper limit normal. This study should not be interpreted as evidence to avoid thrombolysis in submassive PE but rather as evidence that full-dose tenecteplase may be excessive and that heparin should be used very carefully in patients who receive thrombolysis. Using 50mg alteplase and meticulously avoiding supratheraputic heparin infusions may be the key to success as revealed in two recent publications by the MOPETT investigators.

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The dogmas that heparin infusions are safe, that alteplase is extremely dangerous in PE patients, and that heparin is the first-line therapy for submassive PE need to be challenged. The Cochrane review of heparin for management of PE in 2006 concluded that although there is little evidence to support heparin, its wide acceptance would make it difficult to perform a RCT comparing heparin to placebo. Perhaps the time has come for a RCT comparing heparin to 50mg alteplase as initial therapy for submassive PE.

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Notes

[1] One of the arguments against giving thrombolytics in PE is that the patients may “look too good” to require aggressive treatment. PE is notorious for causing patients to go from looking fine to PEA arrest within minutes. I’ve had the unfortunate opportunity to see this – even patients who are observed in the ICU initially and seem to be doing well may later arrest. A septic patient who is “looking good” after ICU observation will likely do well, whereas a PE patient who looks well may still be at risk for cardiovascular collapse.
[2] Smart EM podcast on PE, Cochrane Review of anticoagulants in treatment for acute venous thromboembolism.
[3] Methodology for constructing the tables: most of the data from the tables is based on the Cochrane Review of thrombolysis for PE published in 2009. All relevant studies which met the Cochrane standards were included in the table with the exception of Goldhaber et al 1993 (One patient had an ICH in this study: she had a head injury and should have been excluded from the study but she was included erroneously, randomized to the heparin group, and later crossed over to the alteplase group.) Literature search was used to look for more recent studies from 2009-2014. It should be noted that some of the earlier studies included patients who would not be considered candidates for thrombolysis today.
[4] Tardy B et al. Thrombosis Research 2009.
[5] Some studies may have used slightly different definitions of major hemorrhage, but this should provide a reasonable concept of what the data looks like.
[6] Alteplase and tenecteplase have different half-lives, so it’s not accurate to compare them on a milligram-per-milligram basis. For the purposes of this post I’m defining “full-dose” as the same dose used to thrombolyse a myocardial infarction.
[7] Yes, I know, comparing event rates between different populations is a stretch. I included these statistical calculations to give the readers a roughsense of what the statistics might look like. Although my comparisons here are admittedly indirect and of dubious statistical validity, what is clear is that it cannot be assumed that results obtained with PEITHO will apply to half-dose alteplase.
[8] Wang et al. 2010
[9] The editorial states “Another approach to reduce bleeding risk that has been studied in the management of myocardial infarction but not, as far as I know, in the management of pulmonary embolism is the use of half-dose fibrinolysis for patients 75 years of age or older” (NEJM 2014; 370: 1457).

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Mike Scott

Noticed in this trial that they report ALL strokes, and then specifically number of those that were hemorrhagic (12 and 10 in PEITHO, respectively). Have seen this in some of the lytics for MI trials as well. Do you know of any reason why we would expect an increase in ischemic stroke due to lytics? Or wy else they would report it as all and hemorrhagic strokes rather than just reporting ICH? Great work, as usual!

Thank you Josh for this review. I am a chest physician in the UK. Can i clarify your thoughts regarding the use of heparin before thrombolysis infusion. Invariably there is some delay before confirming the diagnosis of PE, and getting all the prognostic info to base ones decision regarding reperfusion (ie echo, biomarkers, leg US).
Heparin is usually given as LMWH (full treatment dose) at the outset during this time. How would this fare in terms of bleeding risk – Full treatment dose LMWH initially, then reduced dose thrombolysis infusion over 2 hours, then start unfractionated heparin infusion 12 hours after initial LMWH dose aiming to maintain APTT ratio 1.5-2.
Thanks
Rizwan

What's Your Job?

consultant chest physician

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5 months ago

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Matt Anderson

TOPCOAT totally disagree. First, unless I missed something, we have no baseline for any of these patients (I get it would be hard to predict getting a submassive PE- but no hart review, or even biased questionnaire to compare previous health- which maybe the ones they used did- but there was no sig difference either way). Second, this is a composite end point- looking at the NS point it al appears to be related to subjective parameters which within a study of 83 patients, you can’t find anything all that meaningful. Third, only stat sig 90d follow up difference – subjective assessment of Heath (1- real bad, 10- I’m awesome), tenectaplse ~3, heparin ~2 — this would tell me these patients probably weren’t running marathons with a score of ~3 (over blown functional benefits that are being perpuated). I’d guess if their subjective QOL was a ~3, they probably weren’t doing that great before (my guess if you look retrospectively at these patients the NYHA III pts who walk less than <330m on a 6 MWT (other 2 mod diff on table 4)–they probably had underlying disease prior). I agree there's a group of submassive PE that deserves lytics (25… Read more »